rs150941761

chr22-41170430-A-Cchr22-41170430-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001429.4(EP300):c.4311A>C(p.Ala1437=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,844 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (15 hom.)
• Consequence: EP300 NM_001429.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.956

Genes affected

EP300 (HGNC:3373): (E1A binding protein p300) This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 22-41170430-A-C is Benign according to our data. Variant chr22-41170430-A-C is described in ClinVar as [Benign]. Clinvar id is 341805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.956 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00181 (275/152238) while in subpopulation EAS AF= 0.0161 (83/5168). AF 95% confidence interval is 0.0133. There are 2 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.4311A>C	p.Ala1437=	synonymous_variant	27/31	ENST00000263253.9
EP300	NM_001362843.2	c.4233A>C	p.Ala1411=	synonymous_variant	26/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.4311A>C	p.Ala1437=	synonymous_variant	27/31	1	NM_001429.4	P2
	ENST00000415054.1	n.83-849T>G		intron_variant, non_coding_transcript_variant		3
EP300	ENST00000674155.1	c.4233A>C	p.Ala1411=	synonymous_variant	26/30			A2
EP300	ENST00000703544.1	c.*2231A>C		3_prime_UTR_variant, NMD_transcript_variant	26/30

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152118 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.00375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00264 AC: 665 AN: 251470 Hom.: 4 AF XY: 0.00269 AC XY: 365 AN XY: 135908

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0133

Gnomad SAS exome AF: 0.00441

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00173 AC: 2522 AN: 1461606 Hom.: 15 Cov.: 32 AF XY: 0.00190 AC XY: 1381 AN XY: 727102

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0221

Gnomad4 SAS exome AF: 0.00432

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000847

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152238 Hom.: 2 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74436

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0161

Gnomad4 SAS AF: 0.00375

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000941 Hom.: 0

Bravo AF: 0.00233

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00207

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	EP300: BP4, BP7, BS1, BS2 -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

EP300-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.7
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150941761; hg19: chr22-41566434; COSMIC: COSV54327284; COSMIC: COSV54327284;